Abstract

Background

Metformin is widely used in the treatment of diabetes, and there is interest in ‘repurposing’
the drug for cancer prevention or treatment. However, the mechanism underlying the
metabolic effects of metformin remains poorly understood.

Methods

We performed respirometry and stable isotope tracer analyses on cells and isolated
mitochondria to investigate the impact of metformin on mitochondrial functions.

Results

We show that metformin decreases mitochondrial respiration, causing an increase in
the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells
treated with metformin become energetically inefficient, and display increased aerobic
glycolysis and reduced glucose metabolism through the citric acid cycle. Conflicting
prior studies proposed mitochondrial complex I or various cytosolic targets for metformin
action, but we show that the compound limits respiration and citric acid cycle activity
in isolated mitochondria, indicating that at least for these effects, the mitochondrion
is the primary target. Finally, we demonstrate that cancer cells exposed to metformin
display a greater compensatory increase in aerobic glycolysis than nontransformed
cells, highlighting their metabolic vulnerability. Prevention of this compensatory
metabolic event in cancer cells significantly impairs survival.

Conclusions

Together, these results demonstrate that metformin directly acts on mitochondria to
limit respiration and that the sensitivity of cells to metformin is dependent on their
ability to cope with energetic stress.